Novel Agent Shows Early Promise for Advanced Myelofibrosis


Results of the phase 2 MANIFEST study presented at ASH 2019 suggest CPI-0610 could be an effective treatment for patients with refractory or intolerant advanced myelofibrosis.

John Mascarenhas, MD

John Mascarenhas, MD

The novel BET inhibitor CPI-0610 was effectively added to standard of care ruxolitinib (Jakafi) for patients with advanced myelofibrosis, with almost half of patients capable of stopping regular blood transfusions for their disease at a 24-week analysis, according to updated findings from the phase II MANIFEST trial presented at the 2019 ASH Annual Meeting.1

The addition of CPI-0610 to ongoing treatment with ruxolitinib, resulted in a 24.9% reduction in spleen volume at 24 weeks and a 58.8% improvement in total symptom score (TSS) for transfusion dependent (TD) patients with myelofibrosis. Additionally, 43% of patients converted from being TD to transfusion independent (TI) following treatment with the combination.

"Among evaluable patients who were transfusion dependent on ruxolitinib, 6 of 14 patients converted to transfusion independence after the addition of CPl-0610 in the study,” John Mascarenhas, MD, Tisch Cancer Institute, Division of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, said during a presentation of the results. “Symptom responses were seen in a majority of patients, we know this because they told us, we treated these patients and they did much better.”

The MANIFEST trial included multiple treatment arms, each looking at cohorts of TD and TI patients. Arm 1 of the study examined single-agent CPI-0610 following prior treatment with ruxolitinib (n = 36). In arm 2 of the study, CPI-0610 was added to ruxolitinib for patients already receiving the JAK/STAT inhibitor for at least 6 months (n = 54). Arm 1 of the study included cohort 1A, in which patients were TD. Cohort 1B within this same group included those who were TI. In arm 2, patients included in cohort 2A of this group were TD and cohort 2B were TI.

Of those who transitioned from TD to TI, 36.4% in the combination arm had bone marrow improvement. A 1 grade improvement in bone marrow fibrosis was seen in 38% of patients analyzed, with most of these occurring within 6 months of treatment (83%).

Across both groups, 83.3% of patients continued on the study at the time of the analysis. The primary reason for discontinuation was progressive disease (5.6%) or death (5.6%). The median treatment duration was 16.2 weeks, and 41.1% of patients have been on treatment for 24 weeks or longer.

In arm 2 looking at CPI-0610 added to ruxolitinib, a spleen volume response with at least 35% reduction in spleen size (SVR35) at week 24 was experienced by 25% of TD patients. Additionally, a TSS reduction of ≥50% (TSS50) at week 24 was experienced by 54% of TD patients. Seventy-five percent of patients noted an improvement in overall status by patient global impression of change (PGIC) scores. In TI patients treated with the combination, the SVR35 rate was 0 and the TSS ≥50% response was 38% at 24 weeks. In this group, there was a 69% improvement in PGIC score, with 46% of patients saying their overall status was much or very much improved.

In arm 1 looking at CPI-0610 monotherapy, the SVR35 was 0 and there was a median reduction in spleen size of 3.2% in TD patients. TSS ≥50% was 0 with the single agent, with a mean reduction from baseline of 18.4%. The PGIC score improved by 50%. In TI patients in arm 1, the SVR35 was 0 and the median change in spleen reduction was 26%. TSS ≥50% occurred in 60% of patients, with a median reduction of 53.5%. At 24 weeks, there was a 100% improvement in PGIC scores, with more than half of patients saying they were much improved (57%).

In the monotherapy and combination groups, respectively, 55% and 13% of patients had improvements of ≥1.5 g/dL in hemoglobin counts. Bone marrow fibrosis was improved from baseline to subsequent bone marrow biopsy for 22.2% and 43.5% of patients in the monotherapy and combination groups, respectively. Both hemoglobin and bone marrow fibrosis improvements were seen in 22.2% and 17.4% of patients, in the single-agent and combination arms, respectively.

The most common all-grade, all-cause adverse events (AEs) were diarrhea (32.2%), thrombocytopenia (23.3%), nausea (22.2%), cough (16.7%), vomiting (14.4%), fatigue (14.4%), and upper respiratory tract infection (14.4%). Non-hematologic AEs were primary grade 1/2 in severity, Mascarenhas noted.

The most common grade ≥3 AEs were thrombocytopenia (10%), anemia (6.7%), diarrhea (4.4%), and fatigue (3.3%). None of the grade ≥3 cases of thrombocytopenia were deemed serious, Mascarenhas noted. Across the 90 patients enrolled in the study, 8 experienced a grade 4 AE (8.9%). There were 3 grade 5 events (3.3%), which were not considered related to CPI-0610. These events all occurred in arm 2 of the study.

"CPl-0610 as monotherapy and as add-on was generally well tolerated. Thrombocytopenia was observed and asymptomatic. It was generally reversible and manageable and there were no additional unanticipated safety concerns observed," said Mascarenhas.

Based on findings from the first arms of the study, cohort 2A was expanded to enroll an additional 60 patients for the combination of CPl-0610 and ruxolitinib. Additionally, arm 3 of the study, which was not presented as part of this presentation, is looking at the combination of CPI-0610 with ruxolitinib in untreated patients with myelofibrosis. Based on these preliminary findings, cohort 3 of the study is being expanded to enroll up to 101 patients (NCT02158858).


Mascarenhas J, Kremyanskaya M, Hoffman R, et al. MANIFEST, a Phase 2 Study of CPI-0610, a Bromodomain and Extraterminal Domain Inhibitor (BETi), As Monotherapy or “Add-on” to Ruxolitinib, in Patients with Refractory or Intolerant Advanced Myelofibrosis. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 670.

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